The present invention relates to 1H-indole derivatives as a highly selective cyclooxygenase-2 inhibitor.
Most of non-steroid anti-inflammatory drugs represent actions such as anti-inflammation, ataralgesia, defervescence by inhibiting the enzymatic activity of cyclooxygenase or prostaglandin G/H synthase. In addition, they can suppress the uterine contraction induced by hormones and the cell proliferation in several kinds of cancers. First, only cyclooxygenase-1 was known to be found in cow as a constitutional enzyme. But recently, cyclooxygenase-2 is elucidated as an induced form. Cyclooxygenase-2 is identified to be discriminated clearly from cyclooxygenase-1 and can be provoked easily by mitogen, endotoxin, hormones, growth factors, cytokines and the like.
Prostaglandins have various pathological and physiological functions. Precisely, cyclooxygenase-1 as a constitutional enzyme participates in the secretion of basic endogenous prostaglandin and plays an important role in physiological aspects such as stomach homeostasis, renal blood circulation and so on. On the other hand, cyclooxygenase-2 is induced by inflammatory factors, hormones, growth factors, cytokines and the like and thus plays an important role in pathological effects of prostaglandins. Therefore, selective inhibitors against cyclooxygenase-2 are expected to have no side effect on account of the functional mechanism compared with the anti-inflammatory drugs such as conventional non-steroid agents and to represent actions such as anti-inflammation, ataralgesia and defervescence. Furthermore, it is estimated to suppress the uterine contraction induced by hormones and the cell proliferation in several kinds of cancers. Especially, it probably has lesser side effects such as gastrointestinal toxicity, renal toxicity and the like. Also, it is assumed to prevent the synthesis of contractive prostanoids and thus inhibit the contraction of smooth muscle induced by the prostanoid. Hence, it can be applied usefully to treat a premature birth, dysmenorrhea, asthma and several diseases associated with eosinophilic leukocytes. Besides, it can be exploited widely to cure osteoporosis, glaucoma and athymia, which has been disclosed in a lot of references, especially the usefulness of selective inhibitors against cyclooxygenase-2 (References: John Vane, xe2x80x9cTowards a better aspirinxe2x80x9d in Nature, Vol. 367, pp 215-216, 1994; Bruno Battistini, Regina Botting and Y. S. Bakhle, xe2x80x9cCOX-1 and COX-2; Toward the Development of More Selective NSAIDsxe2x80x9d in Drug News and Perspectives, Vol. 7, pp 501-512, 1994; David B. Reitz and Karen Seibert, xe2x80x9cSelective Cyclooxygenase Inhibitorsxe2x80x9d in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, pp 179-188, 1995).
The selective inhibitors against cyclooxygenase-2 have been reported to have various structural forms. Among these, the diaryl heterocycle structure, namely a tricyclic system, has been studied most frequently and exploited to construct a lot of candidate substances. In this structure, it is essential that sulfonamide or methanesulfone group exist onto one phenyl group. The initial substance of such a structure is identified to be Dup697 (Bioorganic and Medicinal Chemistry Letters, Vol. 5, No. 18, p 2123, 1995). Then, as a derivative, SC-58635 (Journal of Medicinal Chemistry, Vol. 40, p 1347, 1997) having a pyrrazole structure, MK-966 (WO 95/00501) having a furanone structure and the like are disclosed.
Based upon the above technical backgrounds, the inventors of the present invention have tried a lot in order to develop novel compounds as a highly selective cyclooxygenase-2 inhibitor. As a result, we have found that 1H-indole derivatives of formula 1 satisfied such a purpose and completed the present invention successfully.
Therefore, the object of the present invention is to provide 1H-indole derivatives of formula 1 and its pharmaceutically acceptable salts as depicted below.
Hereinafter, the present invention will be described more clearly.
The present invention relates to 1H-indole derivatives of formula 1 and its pharmaceutically acceptable salts. 
Wherein, - - - is a double bond or a single bond, X is NO2, NH2, or xe2x80x94NHSO2R wherein R represents hydrogen or C1-C3-alkyl, Y is hydrogen, halogen, C1-C3-alkyl substituted or not substituted by halogen, NO2, NH2, OH, OMe, CO2H, or CN, Q is Cxe2x95x90O, Cxe2x95x90S, or CH2.
The compound of the present invention can exist as a pharmaceutically acceptable salt form, wherein the pharmaceutically acceptable salt means a nontoxic salt containing organic salt and inorganic salt and accepted pharmaceutically. The inorganic salt consists of aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc and the like and preferably, ammonium, calcium, magnesium, potassium, sodium. The organic salt consists of primary-, secondary- or tertiary-amines, naturally substituted amines, cyclic amines, modified salts prepared through a basic ion exchange resin and the like. Preferably, the organic salt can be selected among arginine, betain, caffeine, colin, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, N-methylglucamine, glucamine, glucosamine, histidine, hydrapamine, N-(2-hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procain, purine, teobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Besides, the compound of the present invention can be a salt form of nontoxic acids containing the organic acid and the inorganic acid and accepted pharmaceutically, in case that it be basic. Preferably, the acid can be adopted among acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzenesufonic acid, benzo acid, camposulfonic acid, citric acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, ethylendiaminetetraacetic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydriodic acid, hydrobromic acid, hydrochloric acid, icethionic acid, lactic acid, maleic acid, malic acid, manderic acid, methanesulfonic acid, music acid, 2-naphthalene disulfonic acid, nitric acid, oxalic acid, parnoic acid, pantothenic acid, phosphoric acid, pivalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, 10-undecenoic acid and the like and more preferably, among succinic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, phosphoric acid, sulfuric acid, tartaric acid and the like.
Preferably, the compound of the present invention of formula 1 as a selective inhibitor against cyclooxygenase-2 is that X is NO2, NH2, or xe2x80x94NHSO2CH3, Y is hydrogen, halogen, C1-C3-alkyl, or OMe, and Q is Cxe2x95x90O or CH2.
For preferred embodiments of the present invention, the compounds of formula 1 will be described more clearly as follows:
1-benzoyl-5-nitro-1H-indole;
1-benzyl-5-nitro-1H-indole;
1-(4-fluoro-benzyl)-5-nitro-1H-indole;
1-(4-methoxy-benzyl)-5-nitro-1H-indole;
1-(4-isopropyl-benzyl)-5-nitro-1H-indole;
1-benzoyl-5-amino-1H-indole;
N-(1-benzyl-1H-indole-5-yl)-methanesulfonamide;
N-[1-(4-fluoro-benzyl)-1H-indole-5-yl]-methanesulfonamide;
N-(l-benzoyl-1H-indole-5-yl)-methanesulfonamide;
1- benzyl-5-nitro-2,3-dihydro-1H-indole;
N-(l-benzyl-2,3-dihydro-1H-indole-5-yl) methanesulfonamide; and
N-(1-benzoyl-2,3-dihydro-1H-indole-5-yl)-methansulfonamide.
On the other hand, the compounds of formula 1 in the present invention can be prepared by performing the procedures as illustrated below.
However, the process for preparing the compounds of the present invention will not be restricted to following descriptions, especially in reaction solvents, bases, amounts of used reactants and the like.
Moreover, the compound of the present invention also can be prepared by exploiting and combining various synthetic methods described in the present specification or disclosed in other references of those skilled in this arts with a coordinate and arbitrary mode.
Those skilled in the art will appreciate that the conceptions and specific embodiments disclosed in the foregoing description may be readily utilized as a basis for modifying or designing other embodiments.
Concretely, the compound of formula 1 in the present invention can be prepared as illustrated schematically in following reaction formula 1. 
Wherein, - - - , X, Y, and Q are defined above, L is halogen.
As demonstrated in the above reaction formula 1, the compound of the present invention can be prepared through 2 pathways from 5-nitroindole or 5-nitroindoline as initial material. Namely, benzoyl group or benzyl group are introduced to a nitrogen atom included in the parent nucleus first and then, methanesulfonyl group is inserted to an amine group on 5-location (method 1). On the other hand, methanesulfonyl group is adopted to an amine group on 5-location of parent nucleus first, and then benzoyl group or benzyl group are introduced later (method 2).
A detailed description on preparing the compound of the present invention by the above method (1) is as follows.
The reaction of 5-nitroindole or 5-nitroindoline with benzoylhalide or benzylhalide derivatives should be specifically accomplished under the presence of a base. Concretely, the reaction is performed at the range of room temperature xcx9c80xc2x0 C. by using dimethylformamide. At this moment, the organic base can be selected among triethylamine, trimethylamine, tripropylamine, pyridine, imidazole, and the like, while the inorganic base can be selected among sodiumacetate, sodium hydroxide, sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, and the like. More preferably, potassium carbonate can be adopted.
The reaction reducing from nitro to amine is performed under the presence of palladium/carbon and ammonium formate as a catalyst at the range of room temperature xcx9c80xc2x0 C. by using a single or mixed solvent selected among tetrahydrofuran, diethylether, dimethoxyethane, ethylacetate, dichloromethane, methanol, and ethanol.
The reaction forming sulfonamide is accomplished as follows: amine and mesyl chloride is reacted under the presence of a base such as triethylamine, trimethylamine, tripropylamine, pyridine, imidazole, and the like by using a solvent selected among tetrahydrofuran, diethylether, dimethoxyethane, ethylacetate, dichloromethane, methanol, ethanol and the like. Preferably, it should be performed at the range of 0xcx9c50xc2x0 C. and more preferably, at a low temperature in between 5xcx9c10xc2x0 C.
On the other hand, a detailed description on preparing the compound of the present invention by the above method (2) is as follows.
The reduction of 5-nitroindole or 5-nitroindoline as initial material is performed under the same condition with the above method (1) which exploites palladium/carbon as a catalyst.
Then, the formation of sulfonamide of 5-aminoindole or 5-aminoindoline prepared thereby is accomplished as follows: amine and mesyl chloride is reacted under the presence of a base such as triethylamine, trimethylamine, tripropylamine, pyridine, imidazole, and a solvent selected among tetrahydrofuran, diethylether, dimethoxyethane, ethylacetate, dichloromethane, methanol, and ethanol. Preferably, it should be performed at the range of xe2x88x9230xc2x0 C.xcx9croom temperature and more preferably, at a low temperature in between xe2x88x9220xcx9cxe2x88x9210xc2x0 C.
The resulting sulfonamide compound will be reacted with bezoylhalide or benzylhalide derivatives through the following procedure. The reaction solvent can be a non-reactive solvent such as dichloromethane, diethylether, tetrhydrofuran, and the like. At this moment, the reaction temperature should be preferably at the range of xe2x88x9230xcx9c20xc2x0 C. and more preferably, at a low temperature in between xe2x88x9220xcx9cxe2x88x9210xc2x0 C. A base should be exploited for this reaction, which can be selected among triethylamine, trimethylamine, tripropylamine, pyridine, imidazole and the like as an organic base and among sodium acetate, sodium hydroxide, sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate and the like as an inorganic base, more preferably sodium hydride.
After completing the reaction, the resulting products can be processed through a common treatment such as chromatography, re-crytallization and the like so as to be separated and purified.
The compound of the present invention depicted in formula 1 has an activity for the selective inhibition against cyclooxygenase-2 and thus can be utilized as an enzymatic inhibitor. The compound of formula 1 having a selective inhibitor against cyclooxygenase-2 can be a substitute for conventional non-steroid anti-inflammatory drugs and especially the compound is useful in patients suffering from peptic ulcer, gastritis, partial enteritis, ulcerative colitis, diverticulitis, gastrointestinal haemorrhagia, hypoprothrombinemia and the like as substitute drugs improved in side effects of conventional non-steroid anti-inflammatory drugs. Besides, it is expected to treat inflammatory diseases such as osteoarthritis, rheumatoid arthritis and the like effectively.
The compound of the present invention can be administered in a single dose or in separated doses, depending upon clinical purposes. The specific dosage for patients will vary, depending upon factors such as a sort of drug compound, body weight, sex, physical condition, diet, administration period, administration method, discharge ratio, drug composition and severity of diseases and the like.
The compound of the present invention can be administered as an oral, a local, a parenteral (subcutaneous, venous and muscular silinge or injection), an inhalational or a rectal drug. In case that these are prepared to a pharmaceutical drug, one or more commonly used vehicles, methods for the preparation and the like can be adopted properly from prior arts widely reported to those skilled.
In order to attain the desired purpose of clinical administration, the active compound of formula 1 in the present invention can be administered coincidently by combining more than one component of other commercial drugs.
However, the pharmaceutical drugs containing the compound of the present invention is not limited to forms described above, if it has a purpose for inhibiting cyclooxygenase-2 selectively. All kinds of drugs useful for the enzymatic inhibition can be within the scope of the present invention.